Colorectal cancer (CRC) is one of the most common cancers in both men and women in the United States, and comprises about 10% of new cancer cases. Colorectal cancer is an age-related epithelial cancer that often takes over twenty years to progress from initial benign adenoma (polyp) to invasive adenocarcinoma. The majority of colon cancers are characterized by genetic mutations in adenomatous polyposis coli (APC) or (-catenin, two key components of the Wnt signaling pathway. In the absence of Wnts, (-catenin is normally targeted for degradation by the GSK-3/Axin/APC complex. In the presence of Wnts, this degradation pathway is inhibited, (-catenin accumulates in the cytoplasm and nucleus and binds and transactivates Tcf/Lef proteins. Tcf4 is a member of the Tcf/Lef family of transcription factors. We will rigorously test, via gain and loss of functions studies in the mouse, the role of Tcf4-expressing cells and Wnt-(-catenin signaling on the development and maintenance of intestinal epithelial cells in normal and tumor cells during embryogenesis and in adulthood. Results from our experiments will give us important new insights into the etiology of colon cancer and possibly other epithelial cancers.